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Control and regulation of S-Adenosylmethionine biosynthesis by the regulatory β subunit and quinolone-based compounds

DOI: 10.1111/febs.14790 DOI Help

Authors: Jiraporn Panmanee (University of Liverpool) , Jack Bradley-clarke (University of Liverpool) , Jose M. Mato (CIC bioGUNE) , Paul M. O'neill (University of Liverpool) , Svetlana V. Antonyuk (University of Liverpool) , Samar Hasnain (University of Liverpool)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: The Febs Journal , VOL 255

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 11740 , 15991

Open Access Open Access

Abstract: Methylation is an underpinning process of life and provides control for biological processes such as DNA synthesis, cell growth, and apoptosis. Methionine adenosyltransferases (MAT) produce the cellular methyl donor, S-Adenosylmethionine (SAMe). Dysregulation of SAMe level is a relevant event in many diseases, including cancers such as hepatocellular carcinoma and colon cancer. In addition, mutation of Arg264 in MATa1 causes isolated persistent hypermethioninemia, which is characterized by low activity of the enzyme in liver and high level of plasma methionine. In mammals, MATa1/a2 and MATbV1/V2 are the catalytic and the major form of regulatory subunits, respectively. A gating loop comprising residues 113–131 is located beside the active site of catalytic subunits (MATa1/a2) and provides controlled access to the active site. Here, we provide evidence of how the gating loop facilitates the catalysis and define some of the key elements that control the catalytic efficiency. Mutation of several residues of MATa2 including Gln113, Ser114, and Arg264 lead to partial or total loss of enzymatic activity, demonstrating their critical role in catalysis. The enzymatic activity of the mutated enzymes is restored to varying degrees upon complex formation with MATbV1 or MATbV2, endorsing its role as an allosteric regulator of MATa2 in response to the levels of methionine or SAMe. Finally, the protein–protein interacting surface formed in MATa2:MATb complexes is explored to demonstrate that several quinolone-based compounds modulate the activity of MATa2 and its mutants, providing a rational for chemical design/intervention responsive to the level of SAMe in the cellular environment.

Journal Keywords: allosteric regulator; colon cancer; hepatocellular carcinoma; methylation; protein–protein interaction

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: SOLEIL

Panmanee_et_al-2019-The_FEBS_Journal (1).pdf